Journal of Bone and Mineral Research最新文献

Zoledronic acid (ZA), cleared renally, carries a higher nephrotoxicity risk at doses≥4 mg, especially in patients with chronic kidney disease (CKD). While 5 mg is standard for osteoporosis, ZA increases bone mineral density at doses as low as 0.25 mg every 3 mo. Inpatient ZA (IP-ZA) in hip fracture patients reduces mortality and re-fracture risk, but its safety in those with advanced CKD [creatinine clearance rate (CrCl) < 35 mL/min] is unclear. We analyzed real-world data from a large academic healthcare system to assess the safety of reduced-dose IP-ZA (≤3 mg) in hip fracture patients with advanced CKD, compared to propensity-matched controls receiving no anti-osteoporosis medication during index hip fracture hospitalization. The study included 328 IP-ZA patients and 2308 controls, with a primary cohort of 46 IP-ZA patients and 98 matched untreated controls, predominantly female (77.8%), White (92.4%), with a mean age of 89.9 yr and CrCl of 31.1 ± 0.6 mL/min. The IP-ZA group received an average dose of 2.7 ± 0.1 mg (1 patient at 1 mg, 11 at 2 mg, 34 at 3 mg) on postoperative day 2.9 ± 0.3. All patients received standing acetaminophen, calcium (650-1000 mg/d), and vitamin D (1000-2500 IU/d) post-surgery. We monitored daily maximum body temperature, serum creatinine, and serum calcium for five days, starting the day before IP-ZA administration (or postoperative day 2 for controls). IP-ZA did not affect temperature, with new-onset fever (≥38.0 °C, days 2-4) in one IP-ZA patient and two controls. Serum creatinine level remained stable. Serum calcium level in the IP-ZA group decreased from 8.8 ± 0.1 mg/dL to 8.2 ± 0.2 mg/dL by day 5, unchanged in controls; no IP-ZA patient had serum calcium level < 7.5 mg/dL. Hospital length-of-stay (6.2 ± 0.4 vs. 6.5 ± 0.4 d, p = .41) and 30-d readmission rates were similar. This study suggests that reduced-dose IP-ZA is likely safe for patients with hip fracture and advanced CKD who are otherwise at high risk for being untreated.

Introduction: Fracture risk estimates can be used clinically to inform treatment decision-making in osteoporosis. Current fracture risk assessment tools have a low sensitivity in predicting fractures in males. This study aims to evaluate and validate the performance of a new fracture prediction tool - the Microarchitecture Fracture Risk Assessment Calculator (FRAC) - in a multi-centre cohort (MrOS) of older community-dwelling men.

Methods: The performance of FRAC was assessed in a population of 1586 men aged $geq 77$ years in the US. All participants underwent HR-pQCT scanning (61 m) of the distal radius and distal tibia. Incident fracture information was collected every 4 months from the study visit. The FRAC 5-year and 10-year risk of major osteoporotic fracture (MOF) and any osteoporotic fracture (AOF) was calculated for all participants. The model calibration was assessed by fitting Fine Gray competing risk regression models. The model discrimination was assessed using receiver operator characteristic curves (ROCs) and area under the curve (AUCs).

Results: Over the 10-year follow-up period, 129 men experienced an incident major osteoporotic fracture. The FRAC models showed good generalizability of the 5-year risk estimates (regression slope 0.8-1.1) to MrOS cohort. The FRAC models displayed an improved model performance (AUC = 0.685-0.703) relative to reference models of FRAX (AUC = 0.641) and FN aBMD alone (AUC = 0.636) for the 5-year MOF risk estimates. A sub-analysis on individuals classified as moderate risk by FRAX (10-20% MOF risk) found that FRAC aided in stratifying risk, particularly for the 5-year risk estimates (FRAC AUC = 0.691-0.706).

Conclusion: The FRAC models demonstrated strong performance and generalizability to an external cohort of older men. This validation of FRAC suggests its potential use as an alternate assessment tool for osteoporotic fracture risk and may have value in targeting moderate-risk subgroups to aid treatment decisions.

Individuals with dementia have a heightened hip fracture and fall risk but whether markers of brain injury are associated with hip fracture and falls is unknown. We tested the hypothesis that higher circulating brain injury markers were associated with increased risk of hip fracture and fall hospitalizations. Brain injury markers were measured in 2141 participants (mean age 77.9 yr; 60% women). Brain injury markers included neurofilament light chain (NfL), a marker of axonal injury; glial fibrillary acidic protein (GFAP), a marker of astrocytic injury; total Tau, whose many functions include neuron microtubule stabilization; and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), a major protein of neurons. Incident hip fractures and hospitalizations for falls were identified through participant report and confirmed with medical records or medicare claims. Hazard ratios were computed for a doubling exposure (log2 transformed brain injury marker) using multivariable-adjusted Cox models. After a median follow-up of 11 yr, 304 incident hip fractures and 284 incident fall hospitalizations occurred. Doubling of GFAP and NfL were associated with a 22% (p = .048) and 42% (p < .001) higher risk of hip fracture, respectively. Additional adjustment for cognitive function, gait speed, grip strength, inflammatory markers, and depressive symptoms had no effect on results. Models that adjusted for all 4 brain markers showed that only NfL was independent of the other markers. Neurofilament light chain was also associated with a 47% increase risk of hospitalization for falls. There was no association of total Tau or UCH-L1 with hip fracture or falls. GFAP was also unrelated to fall hospitalizations. Neurofilament light chain was independently associated with an incident risk of hip fracture and fall hospitalizations. These results suggest that subclinical degrees of brain injury may contribute to falls and hip fracture. Future research is needed to test whether the association between NfL and hip fracture is independent of falls.

Osteoporosis is a major health concern in older individuals. Efficient case-finding is essential for timely risk assessment and treatment for high-risk patients. To prevent fractures and reduce the risk of subsequent disability, approaches offering clinically sufficient sensitivity with acceptable specificity are warranted. Although pharmaceutical osteoporosis treatment is effective, it is often diagnosed at a late stage, for instance, following a fracture. The aim of this study was to extend the existing Fracture Risk Evaluation Model (FREM), which identifies individuals at risk of an imminent (1-yr) major osteoporotic fracture (MOF) based on administrative health data. This extension (FREMVer2) included data on morbidity and medications and evaluated age-specific risk cut-offs to enhance the risk assessment of MOF and hip fracture (HF) risk, respectively. We included the entire population of Denmark aged ≥45 yr at baseline (2022; N = 2 493 180), not previously diagnosed with osteoporosis or receiving osteoporosis treatment. The cohort was divided into 4 groups stratified by sex and age (<65 yr, ≥65 yr). Each of the 4 groups was randomly split into a 60% development, a 20% model validation, and a 20% cut-off validation cohort. All diagnoses from Danish hospitals and filled prescriptions from Danish pharmacies from 2007 to 2021 were used as possible predictors for MOF. These predictors correspond to information that in Denmark is automatically transferred to general practitioner's electronic health records; hence, prediction would be possible in general practice. Models were constructed by logistic regression with LASSO regularization, determining the preferred regularization hyper parameter by cross-validation and forcing categorical age to be included. Across subgroups, the models obtained poor to acceptable area under the curves (AUCs) of 0.656-0.714 for MOF, and acceptable AUCs of 0.728-0.764 for HFs. Additionally, the models achieved sensitivities of around 80% or higher in almost all subgroups. This performance, together with the available predictors, makes FREMver2 a feasible decision support system as a step toward an opportunistic screening program in health care settings with access to administrative data.

Early-onset osteoporosis (EOOP) is diagnosed in premenopausal women or men under 50 yr of age when DXA-derived BMD is low (Z-score ≤ -2.0 or T-score ≤ -2.5) in the presence of a fragility fracture or a chronic disease. In young adult patients, it is essential to recognize EOOP and identify the underlying cause, including possible genetic defects, to optimize tailored treatments. Among monogenic causes, WNT1-related osteoporosis has been described in children and adults. We present two adults, a 27-yr-old male and his mother, who had no skeletal symptoms in childhood but presented as adults with back pain. Further studies revealed low BMD and multiple spinal fragility fractures, leading to rapid height loss and progressive kyphosis. Biochemistry was largely normal, but bone biopsies showed impaired bone metabolism with low bone turnover. Both were found to harbor a previously described pathogenic heterozygous variant in WNT1, which leads to impaired WNT signaling. We describe the challenges in their clinical care, sequence of treatments, and outcome. These patients highlight the value of a correct genetic diagnosis to better understand the mechanisms behind low bone mass and to enable early intervention. Furthermore, our study emphasizes the need for anabolic treatment options for both males and females with EOOP, and the importance of long-term treatment planning, including an exit strategy.

The Wnt/β-catenin signaling pathway is a classical pathway that regulates bone metabolism. The G protein inhibitory α subunits 1 and 3 (Gαi1/3) can couple with multiple growth factor/cytokine receptors and act as universal adaptor proteins to mediate the activation of key downstream signaling pathways. However, it remains unclear whether and how Gαi1/3 proteins mediate Wnt/β-catenin signal transduction. In this study, we utilized single-cell sequencing analysis and employed viral transfection and gene editing techniques to alter the expression of Gαi1/3 in mouse embryonic osteoblast precursor cells. We examined the relationship between Gαi1/3 expression and the Wnt/β-catenin signaling pathway. Immunoprecipitation and confocal experiments were conducted to further explore the mechanisms by which Gαi1/3 exerts its functions. Osteogenic-related protein levels were detected by Western blotting, and the effects of Gαi1/3 proteins on osteogenic function were examined through alkaline phosphatase and Alizarin red staining. Additionally, micro-CT was used to compare bone mass in mice with different levels of Gαi1/3 expression, showing the relationship between Gαi1/3 and bone formation. Our findings indicate that Gαi1/3 proteins are significantly inversely correlated with age. Gαi1/3, rather than Gαi2, mediates the Wnt/β-catenin signaling pathway and promotes osteogenesis. Mechanistically, Gαi1/3 interacts with Axin1 and recruits it to the cell membrane, leading to inactivation of the β-catenin degradation complex. This results in β-catenin accumulation and nuclear translocation, where it activates the transcription of osteogenic genes. In vivo experiments further confirm that knockdown of Gαi1/3 significantly inhibits bone formation in mice. Our study identified Gαi1/3 as key regulatory proteins in Wnt/β-catenin signaling-mediated osteogenesis, and further elucidated its molecular mechanism in bone formation, which may provide a new therapeutic target for osteoporosis.

Achondroplasia (ACH), the most common skeletal dysplasia in humans, is caused by gain-of-function mutations in fibroblast growth factor receptor 3 (FGFR3). Activation of FGFR3 and its downstream signaling pathways lead to disturbed chondrogenesis in ACH. Nevertheless, the pathogenic mechanism of ACH has yet not been fully elucidated. Previous studies have indicated that FGF and BMP signaling may have opposing actions on the growth plate development. To clarify the crosstalk between FGFR3 and activin receptor-like kinase 3 (ALK3) signaling in ACH, we generated caALK3col2-ACH mice expressing a constitutively active mutant of ALK3 in the chondrocytes of mice with ACH resulting from a Gly369Cys mutation in FGFR3. Unexpectedly, these mice exhibited a more severe chondrodysplasia phenotype than ACH mice, as evidenced by a greater decrease in chondrocyte proliferation and impaired hypertrophy of chondrocytes in the growth plates. These changes were correlated with an increased expression of p21 and activation of ERK/MAPK pathway. This study provides an in vivo genetic demonstration of the imbalanced interaction between the FGFR3 and ALK3 signaling pathways in the growth plate of caALK3col2-ACH mice, suggesting that the ERK/MAPK pathway play an essential role in growth plate chondrogenesis.